1. Newborn Screening for Critical Congenital Heart Diseases (CCHD) Lazaros Kochilas, MD Associate Professor of Pediatrics University of Minnesota

2. Disclosures and Support I will not discuss off label use and/or investigational use in my presentation and I have no conflicts of interest to disclose Pediatric Grand Rounds Lazaros Kochilas, MD

3. …however, I have an interest in the conflict of screening for CCHD! Advocates: Families with CHD Ped. Cardiologists Possible opponents: Delivery Hospitals Third party payers Neutral: Public Health analysts

4. Identify need for screening for CCHD in the nursery Discuss evidence-based recommendations for newborn screening for CCHD Describe efforts for screening implementation on state and national levels Discuss barriers for screening implementation Learning objectives

5. Criteria for using and appraising screening Population: - sufficiently high incidence of screened condition - likely to be compliant Condition: - significant mortality / morbidity - known natural history with detectable presymptomatic period - treatment makes a difference when introduced early Test:- suitable (simple, safe, reliable, validated) - known distribution of values in diseased and non-diseased - acceptable validation process for (+) screens - widely available and acceptable Treatment: - acceptable, available, effective, agreement on whom to treat Program: - adequate staffing/facilities - program is acceptable and effective - acceptable cost - quality management / ongoing re-evaluation

6. Selection Criteria for Newborn Screening Conceptual Framework Definition - Identifiable at birth - Condition characteristics Test characteristics – Treatment - Cost effectiveness

7. Concepts in screening All screening programs do harm; some do good as well Criteria for appraising screening Screening is a program not a test Assess opportunity cost Wilson, J and Jungner, J: Principles and practice of screening for disease: WHO, 1968 Gray, MJ: New concepts in screening; BJ Gen Practice, 2004, 54, 292-298

8. Disease +- Screening adverse effects -AB +CD Particular challenges Limitations of randomized controlled studies Limited evidence to assess benefit/risk ratio Need to calculate opportunity costs “Would you spend $$$ for screening for CHD?” vs. “If you had $$$ to spend for the field of CHD would you spend it for screening?” Public pressure for increasing sensitivity of the testing Challenge of definition

9. Nomination Form HRSA Administrative Review SACHDNC* Evidence Review Group Recommendations to the HHS Secretary Process for addition of new conditions to the uniform panel of newborn screening Not adding to the NBS Additional studies Pilot study Targeted screening Add to NBS Implementation workgroup *Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children

10. oximetry screen 1 st clinical reports Larger prospective study In NY (Koppel) Request to AHA For recommendations AHA comment Evidence not sufficient Proposed bill in TN to mandate screening Several European countries adopt pulse-ox screen as standard of care AHA/AAP statement comment 20022005 Large European prospective studies (Norway, Sweden, UK, Germany, Switzerland) Timeline of pulse oximetry screen for CCHD 20082011 SACHDNC recommended adding pulse-ox screen

11. Definition of the primary target: Critical CHD (CCHD) Requiring surgical, cath or pharmacologic intervention to avoid death or end-organ damage - Hypoplastic left heart syndrome (HLHS) - Pulmonary atresia -Tetralogy of Fallot (TOF) -Total anomalous pulmonary venous return (TAPVR) - Transposition of the great arteries (TGA) - Tricuspid atresia - Truncus arteriosus

12. Current Uniform Screening Panel 29 primary conditions 25 secondary targets -20 metabolic detected by MS (AA, FAO, OA) -3 Hg-pathies (S/S, S/β Thal, S/C) - 6 Others (BIOT, CAH, CF, CH, GALT, HEAR*) -22 metabolic detected by MS (AA, FAO, OA) - 1 Hg-pathies variants - 6 Others (GAL-epimerase, GAL-kinase) * Only point-of-care type of screening

13. CHD: 5-10 / 1,000 live births 1.4 cyanotic CHD / 1,000 live births 2 critical CHD / 1,000 live births 25,000 cases of CHD/yr in US 25% of infantile deaths 31% of neonatal deaths Congenital Heart Diseases: The magnitude of the problem http:// www.cdc.gov/ncbddd/features/heartdefects-keyfindings2010.html Heron, M., et al. (2009). Deaths: Final data for 2006. National Vital Statistics Reports, 57(14). U.S. CDC and Prevention. All together 1.55 /1,000 live births

14. Incidence of CHD

15. 50% of deaths from CHD occur in 1 st year and 50% of infantile deaths occur in 1 st month of life Timing of death from CHD Boneva, R: Circulation. 2001;103:2376

16. Deaths from undiagnosed CHD in Wisconsin 345,573 births (2002-2006) 14 deaths during first 2 wks of life (1: 24,684) Benton, N and Hokanson,J: Missed Congenital Heart Disease in Neonates Congenital Heart Disease 2010; 5(3):292-296

17. Significant physiologic compromise from undiagnosed CHD 490 patients with undiagnosed critical CHD (2000-2003) 76 (15.5%) with significant physiologic compromise 33 (6.7%) preventable Incidence of potentially preventable 1:15,000-1:26,000 Schultz, A: Epidemiologic features of the presentation of critical CHD: implications for screening Pediatrics 2008; 121(4):751-757

18. Missed Critical Congenital Heart Diseases (CCHD) Hoffman, J. It is time for routine neonatal screening by pulse oximetry. Neonatology 2011;99:1-9

19. Types of frequently unrecognized CCHD Hoffman, J. It is time for routine neonatal screening by pulse oximetry. Neonatology 2011;99:1-9

20. Screening for CCHD - Fetal ultrasonography - Physical examination - Pulse oximetry

21. Pulse oximetry as screening method - pulse oximetry measures the amount of O 2 Hgb in the arterial blood - based on differential absorption of O 2 Hgb and RHgb - coupled with ability to separate pulsatile from non-pulsatile components - non-invasive and painless - accurate with newer generation oximeters - “motion resistant” (SET) technology - fast (<2 min) and reliable - inexpensive - peripheral perfusion index (PPI)

22. Distribution of O 2 saturations in 24h newborns with newer generation pulse oximeters de-Wahl Grannelli, A: Acta Paediatrica 2005;94:1590 Critical CHDNewborns

23. O 2 saturation values in patients with CCHD de-Wahl Grannelli, A: Acta Paediatrica 2005;94:1590

24. Reliability in wide range of O 2 saturations de-Wahl Grannelli, A: Acta Paediatrica 2005;94:1590

25. Peripheral perfusion index (PPI) for screening for critical left heart obstructive disease (LVOD) PPI < 0.7 in at least one limb suggesting of LVOD OR 23.8 [95% CI (6.4-88.7)] de-Wahl Grannelli, A: Acta Paediatrica 2007;96:1455

26. Mahle, W et al.: Role of Pulse Oximetry in Examining Newborns for Congenital Heart Disease A Scientific Statement From the AHA and AAP, Circulation 2009; 120:447-458 Studies examining pulse oximetry screening for CCHD - 13 large studies ( > 200,000 newborns ) - Overall test performance >24h: - Sensitivity 70% Specificity 99.9% - False Positive Rate 0.035%False Negative Rate 0.01% - Positive Predictive Value 47%Negative Predictive Value 99.9% - overall improved detection rate vs physical exam alone - improved outcomes?

27. The Swedish prospective study (2004-2007) de-Wahl Grannelli, A: BMJ 2009; 338 W. GötelandContemporary cohortp-value Total46,693108,604 Screened39,821- CCHD Prenatal Dx Clinically / PE (only) Pulse Ox Undiagnosed Deaths 62 2 41/ 5 19 5 0 109 9 72 - 28 0 0.0025* 0.16* Sensitivity62%N/A False positives / FPR69 (0.17%)N/A Specificity99.8%N/A False negatives / FNR11 (0.03%)N/A

28. Screening in Minnesota: Region’s Hospital, Saint Paul Location: Urban (Twin Cities metropolitan area) Number of deliveries:  2,500/year Majority of pregnancies receive prenatal care No high risk pregnancies

29. Start of implementation: 2005 Implemented as new standard of care – No consent Timing: date of discharge (most cases≥ 24h) Cut off for normal ≥ 95% Location of probe: foot Type of probe: reusable No consent No formal f/u procedure Newborn screen by pulse oximetry (Data provided by Larry Condon, MD)

30. Total patients 12,462 Total ECHOs34 (0.27 %) Indications Murmur 22 Syndromes 7 IDM 2 Abnormal screens 3 (0.024%) CCHD 2 (0.016 %) False positives 1 False negatives 0 Screening Results

31. asymptomatic newborns in well baby nursery ≥ 24h of age newer generation pulse oximeters motion resistant technology measuring functional O 2 saturation accuracy (±2% root mean square error) both single use and reusable probes acceptable two sites: right arm and a foot cut-off for positive screen: 3 points (3 times) any value <90% is abnormal cut-off values for areas in high altitude not defined screening incorporated with nursery’s practice and other screening activities Practical considerations

32. Screening Protocol in well baby nursery for asymptomatic newborns >24h or shortly before discharge check pulse ox in right arm and foot in room air Re-screen in 1h 90-94% in both sites or arm-foot difference > 3 points PASSED TEST 90-94% in both sites or arm - foot difference >3 points < 90% in either site Irrespective or difference PCP notified (FURTHER ACTION) ≥ 95% or higher in either site and arm – foot difference ≤ 3 points 90-94 % in both sites or arm-foot difference > 3 points Re-screen in 1h POSITIVE SCREEN DISCHARGE

33. Response suggestions for primary caretaker to failed pulse oximetry screening for Critical Congenital Heart Diseases (CCHD) 1.Confirm accuracy of reading 2. If <24h consider deferring discharge and repeat test at 24h or later; otherwise, follow same algorithm as in older infants 3.Perform additional clinical evaluation to assess for non-cardiac causes 4.Echocardiogram (in-center, transfer, telemedicine) Failed Pulse ox screening: one value equal or less than 90% OR three times 3 points

34. Comparative cost of screening CCHD: 8,000 cases per year in the US Screen will cause additional 8,000 ECHOs per year Cost: $9,000 (5.5-29K) per asymptomatic case diagnosed Metabolic disorders: 6,400 cases per year in the US Cost of metabolic screen $110 / infant X 4 million/year = $440M / yr or $68,750 per patient diagnosed

35. Expected annual activity for Minnesota Minnesota birth rate:70,000 Distribution: 60% access to pediatric cardiology services (50% metro and 10% non-metro cities) Expected positive screens: 46 Expected false positive screens: 25 Need for transfer: 18

36. Estimated financial cost Nursing time: 5-10 min / screen $200K-$400K Pulse oximeter equipment:$100K Pulse oximeter supplies:$200K (reusable) $700K (single use) Echocardiography cost:$70K-200K Transport costs:$50K Estimated total cost:$620K-$950K Additional hospital time / hidden costs:? * Annual Budget - Minnesota Department of Health (MDH) $500M / year ($7.5 M/ year on Newborn Screening)

37. Barriers in implementation Regulatory (informed consent, reusable probes) Cost (equipment, supplies, personnel, transfers, days in hospital) Health care personnel: nursing staff community practitioners echo technicians pediatric cardiologists Equipment: pulse oximeters / ECHO machines & probes Infrastructure & Accessibility Medico-legal concern Skepticism

38. CCHD causes significant morbidity and mortality Newborn screening for CCHD with pulse oximetry is promising Physical examination still useful Early diagnosis of CCHD may improve outcomes Guidelines for implementation of screening have been defined Future refinements likely Pulse Ox screening for CCHD is coming soon to a nursery close to you! Summary